Synthesis
General procedure for the synthesis of indole-6-carbaldehyde from 6-cyanoindole:
1. Preparation of LIX N-[tert-butoxycarbonyl] 2-(1H-indol-6-yl)ethylamine indole-6-carboxaldehyde[6]
- 6-Cyanoindole (15.0 g) and sodium hypophosphite (90 g) were dissolved in a solvent mixture of water (326 mL), acetic acid (326 mL) and pyridine (652 mL).
- Raney nickel catalyst was added and the reaction mixture was stirred at 45°C for 45 minutes.
- Upon completion of the reaction, the mixture was filtered through diatomaceous earth and the filtrate was extracted with ethyl acetate (3 x 500 mL).
- The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure.
- The residue was crystallized by a solvent mixture of dichloromethane and hexane to give 13.6 g (89%) of the target product.MS(EI, m/z): C9H2NO(M+1) 145.9.
2. Preparation of 6-(2-nitrovinyl)-1H-indole [0168]
- Indole-6-carboxaldehyde (2.8 g), nitromethane (30 mL) and ammonium acetate (0.560 g) were mixed and stirred at 100 °C for 30 minutes.
- Excess nitromethane was removed under pressure reduction and the residue was washed with water and dissolved in ethyl acetate (500 mL).
- The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to about 50 mL.
- The suspension was diluted with petroleum ether, filtered and dried to give 3.3 g (91%) of the target product.MS (EI, m/z): C10H8N2O2 (M-1) 186.9.
3. Preparation of 2-(1H-indol-6-yl)ethylamine [689]
- To a solution of 6-(2-nitrovinyl)-1H-indole (1.0 g) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (0.95 g) in one portion and stirred at reflux for 1 hour.
- The reaction was quenched by sequential addition of water (0.95 mL), 15% sodium hydroxide (0.95 mL) and water (2.85 mL).
- The suspension was filtered and the filtrate was diluted with ethyl acetate (200 mL) and washed sequentially with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride.
- The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure.
- The residue was purified by silica gel column chromatography, and the product-containing fractions were combined and concentrated under reduced pressure to give 0.525 g (62%) of the target product.MS (EI, m/z): C10H12N2(M+1) 160.9.
4. Nitrogen protection [0392]
- 2-(1H-indol-6-yl)ethylamine (0.50 g) was dissolved in acetonitrile (25 mL), dimethylaminopyridine and di-tert-butyl dicarbonate (45 mg) were added.
- After stirring at room temperature for 24 hours, the reaction mixture was diluted with ethyl acetate (500 mL).
- The organic phase was washed sequentially with saturated aqueous sodium bicarbonate solution (200 mL), water (2 x 200 mL) and saturated aqueous sodium chloride solution.
- The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure.
- The residue was purified by silica gel column chromatography, eluting with a hexane solution of 20-40% ethyl acetate.
- The product-containing fractions were combined and concentrated under reduced pressure to give 0.42 g (52%) of the target product.MS (EI, m/z): C15H20N2O2 (M-1) 258.9.
